JL 13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b]- [1,5]benzoxazepine fumarate) and JL 3 (10-(4-methylpiperazin-1- yl)pyrido[4,3-b][1,4]benzothiazepine), two pyridobenzazepine derivatives structurally related to clozapine, were selected for further development. Due to their structural similarity to clozapine, they are haunted by the spectre of clozapine-induced agranulocytosis. In a previous study, JL 13 was shown to be less sensitive to oxidation than clozapine. In the present paper, using an in vitro procedure, we report the effect of hypochlorous acid (HOCl), a major in vivo oxidant, on both drugs. It appears that the oxidations of JL 3 and JL 13, unlike clozapine, are very slow and little secondary product is formed. Moreover, in contrast to clozapine, the products that were formed are not reactive and thus do not react with glutathione or N-acetylcysteine. Thus, if, as postulated for clozapine, drug-induced agranulocytosis is due to a reactive metabolite formed by neutrophils or their precursors, JL 3 and JL 13 would not be expected to cause the same adverse reaction. [less ▲]

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various ... [more ▼]

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various hematological disorders, e.g., agranulocytosis. Using five experimental conditions, we tested the oxidative potential of compounds with and without a history of hematological side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and without a history of causing hematologic problems (<70%). The lipid peroxidation system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtained when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4. A multivariate analysis taking into account the five variables provided 87.5% success in classification. The two clusters were better discriminated in terms of a "distance coefficient." In a second analysis, the putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, and JL25) were classified in the cluster of toxic compounds, while the oxa- and thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic compounds. On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herein is, to our knowledge, the first which classifies molecules of different structures as well as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-induced hematological side effects. [less ▲]

The involvement of bradykinin and some other inflammatory mediators in formalin-induced oedema and plasma extravasation was examined. Formalin was injected in rat paws at two doses, 1.75% or 5%. The lower ... [more ▼]

The involvement of bradykinin and some other inflammatory mediators in formalin-induced oedema and plasma extravasation was examined. Formalin was injected in rat paws at two doses, 1.75% or 5%. The lower dose induced the development of an immediate oedema associated with a progressive accumulation of 125I-labelled albumin in the paws. These changes were suppressed by pretreatment with capsaicin or xylocaine. They were abolished by RP67580, a NK1 receptor antagonist, and increased by phosphoramidon or diprotin A. They were not affected by HOE140, a bradykinin B2 antagonist, captopril, methysergide, mepyramine, indomethacin, ketoprofen or L-N(G)-nitroarginine. The higher dose of formalin induced a swelling of the paws which took place in two phases associated with two periods of increase in vascular permeability. This oedema was reduced by pretreatment with capsaicin but not with xylocaine. It was reduced by RP67580 injected before or 30 min after formalin. It was inhibited by mepyramine, methysergide, indomethacin and NS-398, a cyclooxygenase-2 inhibitor. It was not modified by HOE140. Its development was similar in normal and kininogen-deficient rats. We concluded that formalin administered at a low dose induces an oedema which mainly results from a neurogenic inflammation mediated by neuropeptides such as substance P. At higher doses, formalin induces an oedema which mainly depends on the release of substance P, prostanoids, 5-hydroxytryptamine and histamine. Bradykinin plays no significant role in the vascular changes whereas this peptide has been reported to participate in the stimulation of nociceptive afferent neurons. This discrepancy could be explained by a difference in the threshold of stimulation of the nociceptive neurons and that of the cells of the vascular walls, or by a formation of kinins in close contact of the neurons. [less ▲]

The enantioseparation of pirlindole by liquid chromatography (LC) was investigated using three different chiral stationary phases (CSPs) containing either cellulose tris-(3,5-dimethylphenylcarbamate ... [more ▼]

The enantioseparation of pirlindole by liquid chromatography (LC) was investigated using three different chiral stationary phases (CSPs) containing either cellulose tris-(3,5-dimethylphenylcarbamate) (Chiralcel OD-R), ovomucoid (OVM) or beta-cyclodextrin (beta-CD). The effects of the mobile phase pH on retention, enantioselectivity and resolution were studied. Methanol and acetonitrile were tested as organic modifiers while the influence of the addition to the mobile phase of sodium alkanesulfonates or sodium perchlorate was also investigated. Sodium perchlorate was only used on the Chiralcel OD-R column while sodium alkanesulfonates were tested as mobile phase additives on the three kinds of CSPs. The enantioseparation of pirlindole could be obtained on all CSPs tested, the best results with respect to chiral resolution being achieved on the Chiralcel OD-R and the OVM columns. The use of sodium octanesulfonate (NaOS) was found to improve the enantioseparation of pirlindole on the OVM column while enantioselectivity was considerably enhanced by addition of sodium perchlorate on the Chiralcel OD-R column. [less ▲]

Liquid chromatography was employed for the determination of pirlindole enantiomers and its oxidation product dehydropirlindole (DHP). The direct separation of pirlindole enantiomers and DHP was achieved ... [more ▼]

Liquid chromatography was employed for the determination of pirlindole enantiomers and its oxidation product dehydropirlindole (DHP). The direct separation of pirlindole enantiomers and DHP was achieved on a cellulose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase (Chiralcel OD-R). Acetonitrile was used as the organic modifier and sodium perchlorate was used as an ionic additive in the mobile phase. The influence of acetonitrile and sodium perchlorate concentrations on enantioselectivity and achiral selectivity towards DHP was investigated in order to find suitable conditions for the determination of low amounts of each analyte. The mobile phase selected consisted of a mixture of acetonitrile and phosphate buffer (pH 5.0) containing sodium perchlorate (0.05 M) (35:65, v/v) and the UV detector was set at 220 nm. The method developed was validated and was found to be linear in the 0.1-5 microg ml(-1) range (r2 = 0.999 for the three compounds). Repeatability and the intermediate precision for the three analytes at a concentration of 0.1 microg ml(-1) were about 3 and 4%, respectively. This concentration corresponds to the quantification of 0.1% for the minor enantiomer. Actual determinations of enantiomeric purity for single enantiomers of pirlindole were performed. [less ▲]

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic ... [more ▼]

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data. [less ▲]

1. Citicoline (cytidine (5') diphosphocholine) has been shown to reverse aging-induced memory deficits, scopolamine-induced amnesia and nucleus basalis magnocellularis lesion-induced learning impairment. 2. This study aimed to evaluate the effects of citicoline on learning and retrieval processes in a complex differential reinforcement of response duration schedule in normal dogs. 3. The effects of citicoline on a stabilized performance were also measured in order to be able to differentiate specific memory effects from non specific influences on the motor, neuro-vegetative and motivational systems. 4. The results demonstrate that citicoline can exert facilitatory effects on learning and memory but also on retrieval processes. The complete absence of effects on the stabilized performance and on the motor, neuro-vegetative and motivational systems constitutes arguments in favour of a selectivity of action on the memory processes. [less ▲]